Interventional nuclear brain imaging incorporates a variety of radiopharmaceutical techniques to enhance the functional assessment of the central nervous system. Many interventional nuclear brain imaging techniques initially were used in research protocols. In recent years, however, these same challenge paradigms are being increasingly applied with clinical imaging studies. At present, clinical interventional brain imaging techniques include pharmaceutical manipulations with drug administration or withdrawal, physical provocation, electrical stimulation, cognitive activation, and targeting of neurocircuitries with specific molecular receptor-ligand interactions. This review highlights how these approaches have resulted in more accurate measurement of regional cerebral metabolism, delineation of neurocircuitries, presurgical patient selection, and treatment management.